Smooth muscle cell PRDM16 and aortic aneurysm

项目摘要/摘要 主动脉瘤(AA)是一种无症状的疾病，如果发生破裂，死亡率很高(65%~85%)。 通过开放或腔内手术修复是目前主动脉瘤的唯一治疗选择。不是 药物已被批准用于治疗这种毁灭性的疾病。虽然外科手术治疗对 然而，为了防止破裂，它往往与导致严重并发症的外科并发症有关 甚至死亡。因此，再生障碍性贫血仍然是一种威胁生命的疾病。不幸的是，潜在的机制 动脉瘤的发展在很大程度上是未知的，这限制了治疗动脉瘤的药物的开发。 动脉瘤和夹层。这突出表明迫切需要更好地了解动脉瘤的形成和 进步。含16个PR结构域(PRDM16)是一种转录调控因子，在植物生长发育过程中发挥重要作用。 包括造血细胞、心肌细胞和平滑肌细胞在内的细胞的测定和发育。 PRDM16生殖系或血管平滑肌细胞(VSMC)选择性敲除对小鼠的胚胎是致命的， 强调PRDM16在VSMC发育过程中的重要性。目前还不清楚是否 VSMC中PRDM16的表达将影响腹主动脉瘤(AAA)的发展。我们的初步数据 提示AAA患者主动脉中PRDM16基因显著减少，且与PRDM16基因SNP相关 与人类AA破裂有关。他莫昔芬诱导的小鼠VSMC选择性Prdm16基因敲除导致显著 AAA病变中弹性蛋白降解增加。这些数据表明PRDM16功能的丧失促进了 AAA队形。我们进一步发现PRDM16对转化生长的表达具有负性调节作用 β因子(转化生长因子-β)和A去整合素A金属蛋白酶12(ADAM12)在血管内皮细胞中的表达。转化生长因子-β诱导的ADAM12 表达与细胞凋亡呈正相关。此外，共轭亚油酸(CLA)是一种 作为硝化的优先内源底物的omega-3衍生物。有趣的是，口交 CLA和无机亚硝酸盐(NO2)的结合产生内源硝化CLA(NO2-CLA)。No2-CLA是下一代 硝基脂肪酸是人类体内产生的最丰富的脂肪酸。我们的初步数据证明 NO2-CLA稳定PRDM16蛋白，防止体内AAA的形成和发展。此外，NO2- CLA以PRDM16依赖的方式抑制VSMC的凋亡和炎症，这是AAA的两个特征。 因此，我们将具体和系统地解决以下中心假设：“内生生产 在VSMC中，NO2-CLA可通过PRDM16防止AAA的形成和进展。的具体目标 这一建议是为了：1)确定VSMC中的PRDM16阻止AAA的形成和进展；2) 确定PRDM16通过抑制转化生长因子-β/ADAM12信号通路对血管平滑肌细胞功能障碍具有保护作用； 3)确定VSMC内源性产生的NO2-CLA通过PRDM16对AAA具有保护作用。 这项工作将把PRDM16定义为AAA的一个新的治疗靶点，并为开发 可行的口腔治疗新方法..

Project Summary/Abstract Aortic aneurysm (AA) is an asymptomatic disease with high mortality rate (65% to 85%) if rupture occurs. Repair through open or endovascular surgery is currently the only therapeutic option for aortic aneurysm. No drug has been approved for the treatment of this devastating disease. While surgical intervention is effective in preventing rupture, it is however often associated with surgical complications that result in severe morbidity and even mortality. Thus, AA is still a life-threatening disease. Unfortunately, the mechanisms underlying aneurysm development are largely unknown, which is limiting development of medications for treatment of aneurysms and dissections. This highlights an urgent need for better understanding of aneurysm formation and progression. PR domain containing 16 (PRDM16) is a transcriptional regulator and plays crucial roles in the determination and development of cells including hematopoietic, cardiomyocytes and smooth muscle cells. Prdm16 germline or vascular smooth muscle cell (VSMC) selective knockouts are embryonic lethal in mice, highlighting the importance of PRDM16 in the developmental processes of VSMC. It is not yet known whether PRDM16 in VSMC will affect the development of abdominal aortic aneurysm (AAA). Our preliminary data indicate that PRDM16 is significantly reduced in aorta of AAA patients and the PRDM16 SNP is associated with human AA rupture. Tamoxifen-induced VSMC-selective Prdm16 knockout in mice results in a significant increase in elastin degradation in AAA lesions. These data suggest that loss of PRDM16 function promotes AAA formation. We further uncovered that PRDM16 negatively regulates expression of transforming growth factor β (TGF-β) and A disintegrin A metalloprotease 12 (ADAM12) in VSMC. TGF-β induces ADAM12 expression which is positively correlated with cell apoptosis. Additionally, conjugated linoleic acid (cLA) is an omega-3 derivative that serves as the preferential endogenous substrate of nitration. Interestingly, oral delivery of cLA and inorganic nitrite (NO2) yields endogenous nitrated cLA (NO2-cLA). NO2-cLA is a next generation nitro-fatty acid and the most abundant endogenously produced in humans. Our preliminary data document that NO2-cLA stabilizes PRDM16 protein and protects against AAA formation and progression in vivo. Also, NO2- cLA inhibits VSMC apoptosis and inflammation, two hallmarks of AAA, in a PRDM16-dependent manner. Therefore, we will specifically and systematically address the central hypothesis that “endogenous production of NO2-cLA protects against AAA formation and progression through PRDM16 in VSMC”. The specific aims of this proposal are to: 1) determine that PRDM16 in VSMC prevents AAA formation and progression; 2) determine that PRDM16 protects against VSMC dysfunction through inhibition of TGF-β/ADAM12 signaling; and 3) determine that endogenous production of NO2-cLA protects against AAA through PRDM16 in VSMC. This work will define PRDM16 as a novel therapeutic target for AAA and establish the basis to develop a feasible new oral therapeutic approach..